Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029713 (immaturity)
 4,335 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The postnatal development of IPSPs and response to locally applied GABA were examined using intracellular recording techniques in region CA1 of rabbit hippocampal slices maintained in vitro. Pyramidal neurons in slices from mature rabbits demonstrated an EPSP-IPSP sequence following stimulation of stratum radiatum. In these same slices, pressure application of GABA into stratum pyramidale and stratum radiatum produced membrane hyperpolarization and depolarization, respectively. Pyramidal neurons in slices from immature rabbits (age 6 to 10 days) responded differently. Stimulation of stratum radiatum produced a prolonged depolarizing postsynaptic potential; few IPSPs were observed. Ejection of GABA into either stratum pyramidale or stratum radiatum evoked a depolarizing response. The GABA agonist, 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol (THIP), which has been reported to activate "hyperpolarizing" GABA receptors selectively, primarily produced membrane hyperpolarization when applied to the somata of mature neurons, but it evoked a depolarization when applied to immature neurons. Bicuculline, a GABA antagonist which may have a preferential selectivity for "depolarizing" GABA receptors, was somewhat more efficacious (at 50 microM concentration) at antagonizing GABA-evoked depolarization in immature cells than GABA-evoked hyperpolarization in mature cells. This same concentration of bicuculline partially antagonized IPSPs in mature cells, and it markedly potentiated depolarizing PSPs in immature cells. Taken together, these results suggest that the late development of synaptic inhibition in rabbit hippocampus is due, at least in part, to an immaturity in the GABAergic system.
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PMID:Development of hyperpolarizing inhibitory postsynaptic potentials and hyperpolarizing response to gamma-aminobutyric acid in rabbit hippocampus studied in vitro. 670 35

It has been confirmed that a substrain of the senescence-accelerated mouse SAMP1TA/Ngs develops learning disturbance-like behavior at 3 months of age, exhibits almost normal behavior at 5 months, and manifests learning disturbance at 7 months. The changes with age in basal dendrites and dendritic spines of CA1 pyramidal neurons were quantitatively evaluated by the Golgi method using male SAMP1TA/Ngs. The correlation between the change in learning ability and the morphometry was examined. The number of dendritic spines in the 3- and 7-month-old groups was significantly lower than that in the 5-month-old group. It is presumed that the disturbance in acquisition of learning ability at 3 months of age is secondary to the immaturity of neurons, while the learning disturbance at 7 months of age is due to neuronal aging. This substrain, which is characterized by the impairment of acquired learning ability due to senescence, is useful as a model for studies on human brain dysfunction associated with senescence.
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PMID:Age-related changes in basal dendrite and dendritic spine of hippocampal pyramidal neurons (CA1) among SAMP1TA/Ngs--quantitative analysis by the rapid Golgi method. 852 98

Whole-cell voltage clamp techniques were used to characterize the kinetics of INa in immature (P3-5) and older (P > 25) acutely isolated rat CA1 hippocampal neurones. Fast-rising and fast-inactivating currents were recorded at all stages of maturation, evocable from Vm values of -55 to -50 mV. Currents were sensitive to TTX (1 microM) and to sodium removal from the perfusate. Current density and maximum slope conductance increased with maturation. Current decay was described by two exponentials, the faster component dominating at -35 mV or more depolarized Vm values; the ratio fast/slow inactivating component decreased with maturation. The voltage-dependence of conductance was taken as an approximation of m infinity. In younger cells, V1/2 values of the steady-state inactivation (h infinity) and activation curves (m infinity) were depolarized. Shifts of h infinity and m infinity curves were accompanied by shifts in the corresponding tau h and tau m voltage-dependence curves. In younger cells, activation curves had comparatively higher slope factors (Vs), which is an indication of a lower voltage sensitivity of activation. m infinity, tau m, h infinity, and tau h parameters were used to calculate the forward and backward activation and inactivation rate constants (alpha m, beta m, alpha h and beta h). P3-5 cells had relatively higher beta m values accounting for the lower voltage sensitivity of activation. The findings are an indication of a dominant channel variety in the younger cells with a closed state higher probability. The results are consistent with lower depolarization rates previously reported in CA1 cells at early stages of maturation. Faster inactivation due to poor expression of the slower inactivating component may compensate for poorer repolarization mechanisms due to the immaturity of outward currents previously reported at early stages of maturation.
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PMID:The kinetic parameters of sodium currents in maturing acutely isolated rat hippocampal CA1 neurones. 882 77

SAMP1TA/Ngs, a substrain of senescence accelerated mouse, is a useful animal model for research on brain dysfunction due to senescence. In a previous study it was reported that the age-related changes in basal dendrites and spines of CA1 pyramidal neurons coincide with the behavioral characteristics found in SAMP1TA/Ngs. The goal of the present study was to investigate morphological changes in apical dendrites and dendritic spines of CA1 pyramidal neurons among 3-, 5-, 7-month-old SAMP1TA/Ngs. Pyramidal neurons of the hippocampus were stained by the rapid Golgi method, and the number of apical dendrites, the number of their spines and the density of the dendritic spines were evaluated. The number and density of the spines of apical dendrites were significantly higher at 5 months than at 3 or 7 months of age. We propose that the low number of dendritic spines in 3-month-old animals was caused by immaturity, while the changes in the density and number of dendritic spines in 7-month-old mice were due to accelerated aging. The data on the morphology of apical dendrites are a useful complement to the results reported previously. The findings of the present study also support the hypothesis that this model mouse demonstrates changes in respective developmental stages, i.e. immaturity, adulthood and senescence. This pattern of postnatal growth has special meaning because it indicates the usefulness of the strain in the study of geriatric disorders in humans.
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PMID:Quantitative age-related changes in apical dendrites and dendritic spines of CA1 pyramidal neurons among senescence accelerated mice (SAMP1TA/Ngs). 884 49

Previous studies from our group have shown that pentylenetetrazol (PTZ)-induced status epilepticus (SE) leads to age-dependent acute and long-term metabolic and circulatory changes in immature rats. In order to define the neural substrates involved in PTZ seizures according to age, the purpose of the present study was to map the areas of cellular activation during seizures of increasing severity in 10-day-old (P10), 21-day-old (P21) and adult rats. Seizures were induced by repetitive injections of subconvulsive doses of PTZ. The total dose received by the animals ranged from 4 to 125 mg/kg. These doses induced a variety of seizure profiles including absence-like, clonic seizures and SE. The cellular activation was measured as the density of c-Fos immunoreactive cells in animals at 2 h after the onset of the seizures. In P10 rats receiving a behaviourally non-active dose of PTZ, c-Fos immunoreactivity appeared only in the amygdala. The dose of 40 mg/kg that induced absence-like seizures led to a weak c-Fos expression in the medial thalamus, some cortical areas and globus pallidus. Clonic seizures reinforced labelling in the previous areas and induced a spread of c-Fos immunoreactivity to other cortical areas, thalamus, hypothalamus and some brainstem nuclei. At that age, only SE led to a widespread and stronger expression of c-Fos which was, however, totally lacking in the midbrain, and remained incomplete in the brainstem and forebrain limbic system, including the hippocampus. In P21 and adult rats, the inactive dose of PTZ induced c-Fos immunoreactivity in thalamus and hypothalamus. With absence-like seizures, c-Fos labelling spread to the cerebral cortex, amygdala, septum and some brainstem regions. With clonic seizures, immunoreactivity was reinforced in all areas already activated by absence-like seizures, and appeared in the striatum, accumbens, brainstem and hippocampus, except in CA1. After SE, c-Fos was strongly expressed in all brain areas. The intensity of c-Fos labelling was higher in most regions of P21 compared to adult rats. These data are in agreement with the immaturity of cellular and synaptic connectivity in P10 rats, the known greater sensitivity of rats to various kinds of seizures during the third week of life and the nature of the neural substrates involved in PTZ seizures.
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PMID:Mapping of neuronal networks underlying generalized seizures induced by increasing doses of pentylenetetrazol in the immature and adult rat: a c-Fos immunohistochemical study. 975 96

In the CNS, inhibitory synaptic function undergoes profound transformation during early postnatal development. This is due to variations in the subunit composition of subsynaptic GABA(A) receptors (GABA(A)Rs) at differing developmental stages as well as other factors. These include changes in the driving force for chloride-mediated conductances as well as the quantity and/or cleft lifetime of released neurotransmitter. The present study was undertaken to investigate the nature and time course of developmental maturation of GABAergic synaptic function in hippocampal CA1 pyramidal neurons. In neonatal [postnatal day (P) 1-7] and immature (P8-14) CA1 neurons, miniature inhibitory postsynaptic currents (mIPSCs) were significantly larger, were less frequent, and had slower kinetics compared with mIPSCs recorded in more mature neurons. Adult mIPSC kinetics were achieved by the third postnatal week in CA1 neurons. However, despite this apparent maturation of mIPSC kinetics, significant differences in modulation of mIPSCs by allosteric agonists in adolescent (P15-21) neurons were still evident. Diazepam (1-300 nM) and zolpidem (200 nM) increased the amplitude of mIPSCs in adolescent but not adult neurons. Both drugs increased mIPSC decay times equally at both ages. These differential agonist effects on mIPSC amplitude suggest that in adolescent CA1 neurons, inhibitory synapses operate differently than adult synapses and function as if subsynaptic receptors are not fully occupied by quantal release of GABA. Rapid agonist application experiments on perisomatic patches pulled from adolescent neurons provided additional support for this hypothesis. In GABA(A)R currents recorded in these patches, benzodiazepine amplitude augmentation effects were evident only when nonsaturating GABA concentrations were applied. Furthermore nonstationary noise analysis of mIPSCs in P15-21 neurons revealed that zolpidem-induced mIPSC augmentation was not due to an increase in single-channel conductance of subsynaptic GABA(A)Rs but rather to an increase in the number of open channels responding to a single GABA quantum, further supporting the hypothesis that synaptic receptors may not be saturated during synaptic function in adolescent neurons. These data demonstrate that inhibitory synaptic transmission undergoes a markedly protracted postnatal maturation in rat CA1 pyramidal neurons. In the first two postnatal weeks, mIPSCs are large in amplitude, are slow, and occur infrequently. By the third postnatal week, mIPSCs have matured kinetically but retain distinct responses to modulatory drugs, possibly reflecting continued immaturity in synaptic structure and function persisting through adolescence.
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PMID:Protracted postnatal development of inhibitory synaptic transmission in rat hippocampal area CA1 neurons. 1106 89

Organotypic hippocampal slices were prepared from postnatal day 4 rats and maintained in culture for >6 weeks. Cultured slices exhibited from 12 days in vitro spontaneous events which closely resembled giant depolarizing potentials (GDPs) recorded in neonatal hippocampal slices. GDP-like events occurred over the entire hippocampus with a delay of 30-60 ms between two adjacent regions as demonstrated by pair recordings from CA3-CA3, CA3-CA1 and interneurone-CA3 pyramidal cells. As in acute slices, spontaneous recurrent events were generated by the interplay of GABA and glutamate acting on AMPA receptors as they were reversibly blocked by bicuculline and 6,7-dinitroquinoxaline-2,3-dione but not by dl-2-amino-5-phosphonopentaoic acid. The equilibrium potentials for GABA measured in whole cell and gramicidin-perforated patch from interconnected interneurones-CA3 pyramidal cells were -70 and -56 mV, respectively. The resting membrane potential estimated from the reversal of N-methyl-D-aspartate-induced single-channel currents in cell-attach experiments was -75 mV. In spite of its depolarizing action, in the majority of cases GABA was still inhibitory as it blocked the firing of principal cells. The increased level of glutamatergic connectivity certainly contributed to network synchronization and to the development of interictal discharges after prolonged exposure to bicuculline. In spite of its inhibitory action, in a minority of cells GABA was still depolarizing and excitatory as it was able to bring principal cells to fire, suggesting that a certain degree of immaturity is still present in cultured slices. This was in line with the transient bicuculline-induced block of GDPs and with the isoguvacine-induced increase of GDP frequency.
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PMID:Spontaneous recurrent network activity in organotypic rat hippocampal slices. 1602

Loss of oligophrenin1 (OPHN1) function in human causes X-linked mental retardation associated with cerebellar hypoplasia and, in some cases, with lateral ventricle enlargement. In vitro studies showed that ophn1 regulates dendritic spine through the control of Rho GTPases, but its in vivo function remains unknown. We generated a mouse model of ophn1 deficiency and showed that it mimics the ventricles enlargement without affecting the cerebellum morphoanatomy. The ophn1 knock-out mice exhibit behavioral defects in spatial memory together with impairment in social behavior, lateralization, and hyperactivity. Long-term potentiation and mGluR-dependent long-term depression are normal in the CA1 hippocampal area of ophn1 mutant, whereas paired-pulse facilitation is reduced. This altered short-term plasticity that reflects changes in the release of neurotransmitters from the presynaptic processes is associated with normal synaptic density together with a reduction in mature dendritic spines. In culture, inactivation of ophn1 function increases the density and proportion of immature spines. Using a conditional model of loss of ophn1 function, we confirmed this immaturity defect and showed that ophn1 is required at all the stages of the development. These studies show that, depending of the context, ophn1 controls the maturation of dendritic spines either by maintaining the density of mature spines or by limiting the extension of new filopodia. Altogether, these observations indicate that cognitive impairment related to OPHN1 loss of function is associated with both presynaptic and postsynaptic alterations.
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PMID:Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity. 1772 57

Status epilepticus in the immature brain induces neuronal injury in the hippocampal formation, but the mode and mechanism of death are poorly understood. Our laboratory has recently investigated the role of caspase-3, -8, and -9 in neuronal injury, using a lithium-pilocarpine model of status epilepticus in 2-week-old rat pups. Our results showed that dying neurons in the dentate gyrus and CA1-subiculum area do not share the same mechanism of death. In CA1-subiculum, caspase-8 upregulation preceded caspase-3 activation in morphologically necrotic neurons. The pan-caspase inhibitor Q-VD-OPH reduced CA1 damage, showing that caspases contribute to status epilepticus-induced necrosis. In the dentate gyrus, dying neurons were caspase-9 and -3 immunoreactive and morphologically apoptotic. It is not clear why the same seizures cause different types of cell death in neurons that are connected in series along the same hippocampal circuit, but the apoptotic dentate neurons express doublecortin, and do not express calbindin-D28k, suggesting that their immaturity may be a factor in producing an apoptotic mode of death.
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PMID:Distinct caspase pathways mediate necrosis and apoptosis in subpopulations of hippocampal neurons after status epilepticus. 2061 2

While studying the brain function of the human partial epilepsy gene, leucine-rich glioma-inactivated 1 (LGI1), a new mechanism of human epileptogenesis was revealed-persistent immaturity of glutamatergic circuitries. LGI1, a novel secreted protein, was found to be increased during the postnatal period; when glutamatergic synapses both downregulate their presynaptic vesicular release probability and reduce their postsynaptic NMDA-receptor subunit NR2B. During this same period, the dendritic arbor and spines are pruned and remodeled. Using bacterial artificial chromosome transgenic mouse techniques, excess wild-type LGI1 was shown to magnify these critical brain developmental events in the hippocampal dentate gyrus; while an epilepsy-associated, truncated, dominant-negative form of LGI1 blocked them. By contrast, the hippocampal dentate granule neuron GABAergic synapses and intrinsic excitability were unaltered. A role for LGI1 in downregulating glutamate synapse function was confirmed by germline gene deletion; this intervention also revealed a selective increase of glutamatergic synaptic transmission with unaltered GABAergic synapses and intrinsic excitability of hippocampal CA1 pyramidal neurons. Interestingly, the role of LGI1 in neurological disease was further expanded when a subset of patients with limbic encephalitis (an autoimmune disorder with memory loss in 100% and seizures in 80% of individuals) were discovered to carry autoantibodies to LGI1.
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PMID:Arrested glutamatergic synapse development in human partial epilepsy. 2115 44


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